ABSTRACT
Tissue engineering (TE) demands scaffolds that have the necessary resistance to withstand the mechanical stresses once implanted in our body, as well as excellent biocompatibility. Hydrogels are postulated as interesting materials for this purpose, especially those made from biopolymers. In this study, the microstructure and rheological performance, as well as functional and biological properties of chitosan and collagen hydrogels (CH/CG) crosslinked with different coupling agents, both natural such as d-Fructose (F), genipin (G) and transglutaminase (T) and synthetic, using a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride with N-hydroxysuccinimide (EDC/NHS) will be assessed. FTIR tests were carried out to determine if the proposed crosslinking reactions for each crosslinking agent occurred as expected, obtaining positive results in this aspect. Regarding the characterization of the properties of each system, two main trends were observed, from which it could be established that crosslinking with G and EDC-NHS turned out to be more effective and beneficial than with the other two crosslinking agents, producing significant improvements with respect to the base CH/CG hydrogel. In addition, in vitro tests demonstrated the potential application in TE of these systems, especially for those crosslinked with G, T and EDC-NHS.
Subject(s)
Chitosan , Tissue Engineering , Tissue Engineering/methods , Chitosan/chemistry , Hydrogels/pharmacology , Hydrogels/chemistry , Collagen/chemistry , Biopolymers , Cross-Linking Reagents/chemistry , Tissue Scaffolds/chemistry , Biocompatible Materials/pharmacology , Biocompatible Materials/chemistryABSTRACT
The entry into force of the regulation on medical devices obliges clinicians to identify and report to the Health Authorities possible serious incidents arising from their use. In view of the doubts that may arise as to whether or not it may be considered a serious incident, a working group, set up by members of the Spanish Society of Retina and Vitreo and the cluster of ophthalmology and vision sciences (Cluster4Eye) have prepared a document that aims to guide ophthalmologists about some of the incidents that, in the experience of the work team, are not common or can cause serious damage to the patient's function.
Subject(s)
Equipment and Supplies , Ophthalmologic Surgical Procedures , Ophthalmology , Humans , Equipment and Supplies/adverse effects , Eye , Ophthalmologic Surgical Procedures/adverse effects , Government RegulationABSTRACT
Se presenta el caso de un paciente joven de raza caucásica, con una enfermedad renal de causa no clara, con un diagnóstico final establecido por biopsia renal de nefroangioesclerosis benigna evolucionada. Debido a la posibilidad de haber tenido hipertensión arterial en edad pediátrica (sin estudio ni tratamiento), con los hallazgos de biopsia renal, el estudio genético de hipertensión mostró polimorfismos de riesgo en los genes APOL1 y MYH9 y, además, un diagnóstico inesperado de una deleción completa del gen NPHP1 en homocigosis, asociada al desarrollo de nefronoptisis. En conclusión, este caso ilustra la importancia de hacer estudio genético, sobre todo en pacientes jóvenes con enfermedad renal de causa no clara, incluso teniendo un diagnóstico histológico de nefroangioesclerosis. (AU)
We present the case of a young Caucasian patient with renal disease of unclear cause, with a final diagnosis of advanced benign nephroangiosclerosis established by renal biopsy. Due to the possibility of having hypertension in pediatric age (without study or treatment), with the renal biopsy findings, the genetic study showed polymorphisms risk in the APOL1 and MYH9, and also an unexpected diagnosis of a complete deletion of the NPHP1 gene in homozygosis, associated with the development of nephronophthisis. In conclusion, this case illustrates the importance of carrying out a genetic study in youngs patients with renal disease unclear cause, even having a histological diagnosis of nephroangiosclerosis. (AU)
Subject(s)
Humans , Male , Young Adult , Kidney Diseases, Cystic/diagnosis , Hypertension/genetics , Biopsy , Polymorphism, GeneticABSTRACT
We present the case of a young Caucasian patient with renal disease of unclear cause, with a final diagnosis of advanced benign nephroangiosclerosis established by renal biopsy. Due to the possibility of having hypertension in pediatric age (without study or treatment), with the renal biopsy findings, the genetic study showed polymorphisms risk in the APOL1 and MYH9, and also an unexpected diagnosis of a complete deletion of the NPHP1 gene in homozygosis, associated with the development of nephronophthisis. In conclusion, this case illustrates the importance of carrying out a genetic study in youngs patients with renal disease unclear cause, even having a histological diagnosis of nephroangiosclerosis.
Subject(s)
Hypertension , Kidney Diseases, Cystic , Kidney Diseases , Humans , Child , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/pathology , Membrane Proteins , Cytoskeletal Proteins , Adaptor Proteins, Signal Transducing/genetics , Hypertension/genetics , Hypertension/complications , Kidney Diseases/diagnosis , Kidney Diseases/genetics , Apolipoprotein L1ABSTRACT
INTRODUCCIÓN: en esta edición el proyecto CONÓCEME: comprende el medicamento/descubre al farmacéutico, va dirigido también a estudiantes de 4º o 3º Educación Secundaria Obligatoria (ESO) con el fin de llegar a todos los adolescentes.OBJETIVOS: evaluar la diferencia de aprendizaje de las nociones básicas del uso adecuado del medicamento entre los estudiantes de los cursos 1º bachillerato, 4º y 3º ESO. _Evaluar el grado de satisfacción con la actividad educativa de los estudiantes.MATERIAL Y MÉTODOS: estudio observacional descriptivo, transversal, prospectivo, multicéntrico, centrado en una muestra de estudiantes de 1º bachillerato, 4º y 3º ESO de las dos provincias extremeñas durante 2021 y 2022. Se realizaron formaciones específicas a los farmacéuticos comunitarios (FC) que impartieron las intervenciones educativas (IE) informándoles sobre el proyecto, y proporcionándoles la documentación asociada, con la finalidad de conseguir IE lo más homogéneas posibles en todas las provincias. La actividad educativa fue impartida por uno o dos FC, en dos sesiones. Después de cada IE, los estudiantes resolvieron cinco ejercicios en la plataforma del proyecto. En la segunda, tras los ejercicios rellenaron una encuesta de satisfacción. Para completar la actividad se envió al centro el ebook Guía práctica para el uso adecuado de los medicamentos para su difusión entre alumnos y profesores. RESULTADOS: Badajoz fue la provincia de Extremadura que participó en el estudio CONÓCEME, Cáceres se incorporó al proyecto en esta edición 2021. A fecha 11/03/2022, participaron 10 centros educativos, 8 en Cáceres y 2 en Badajoz. Ubicados 7 en población urbana y 3 en rural (<10.000 habitantes); siendo 6 de los centros de titularidad pública. (AU)
Subject(s)
Humans , Pharmaceutical Preparations , Pharmacy , Educational Personnel , Students , Health EducationABSTRACT
HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection.
Subject(s)
HIV Infections , Adult , Expert Testimony , HIV Infections/epidemiology , HumansSubject(s)
Analgesia, Epidural , Analgesia, Obstetrical , Chest Pain/etiology , Female , Humans , Pain Measurement , PregnancyABSTRACT
BACKGROUND: Prognostic factors of long-term survival can guide selection of patients for endovascular repair of abdominal aortic aneurysms (EVAR). The aim of this study was to evaluate the relationship between the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the lymphocyte-to-monocyte ratio (LMR) and the systemic immune-inflammation index (SIII) with survival after EVAR and to assess whether the addition of these biomarkers improved the prediction of survival after surgery. METHODS: Retrospective analysis of 284 consecutive patients who underwent an EVAR at a single institution. The association between biomarkers and survival was explored using generalized additive models with penalized smoothing splines and multivariate Cox models. C-statistics and continuous net reclassification indexes (c-NRI) were used to assess the improvement in prediction. RESULTS: Survival rates at 2 and 5 years were 83.9% and 66.2%, respectively. The predictive score of survival included hemoglobin (HR = 0.849, p = 0.004), statin intake (HR = 0.538, p = 0.004), atrial fibrillation (HR = 2.515, p < 0.001), heart failure (HR = 2.542, p = 0.017) and the non-revascularized coronary artery disease (HR = 2.163, p = 0.004). Spline analyses showed a linear relationship between survival and NLR, PLR, LMR and SII. After adjusting for the predictive score, there was an independent relationship between survival and NLR (HR = 1.072, p = 0.006), PLR (HR = 1.002, p = 0.014) and SII (HR = 1.000, p = 0.043). However, only the addition of NLR improved moderately the c-NRI. A NLR ≥ 3 was independently associated with lower survival rates at 2-years (HR 1.98; 95% CI 1.07-3.66) and 5-years (HR 1.84, 95% CI 1.22-2.78) of follow-up. CONCLUSIONS: Most inflammatory biomarkers are linear and independently associated with survival after EVAR, but only the NLR improved moderately the prediction of a survival score. Therefore, a NLR ≥ 3 may be used to identify patients with a low survival rate and help in decision-making.
Subject(s)
Aortic Aneurysm, Abdominal , Endovascular Procedures , Aortic Aneurysm, Abdominal/surgery , Biomarkers , Humans , Lymphocytes , Male , Neutrophils , Prognosis , Retrospective StudiesABSTRACT
Plasmacytoid dendritic cells (pDCs) are innate immune cells with high antiviral activity triggered by Toll-like receptor 7 (TLR-7) and TLR-9 stimulation. Moreover, they are important mediators between innate and adaptive immunity. Although nowadays there is available an effective therapeutic arsenal against hepatitis C virus (HCV), a protective vaccine is not available. We have analyzed the pDCs' response to HCV infection in a hepatitis C virus (HCV)-Huh7.5 virus-cell system, which allows completion of the virus infectious cycle. pDCs were cocultured following human immunodeficiency virus (HIV) aldrithiol-2 (AT-2 [TLR-7 agonist]) inactivation and CpG (TLR-9 agonist) stimulation. We employed three virus derivatives-wild-type Jc1, interferon (IFN)-resistant virus IR, and high-replicative-fitness virus P100-in order to explore additional IFN-α-related virus inhibition mechanisms. pDCs inhibited HCV infectivity and replication and produced IFN-α. After TLR-7 and TLR-9 stimulation, inhibition of infectivity and IFN-α production by pDCs were enhanced. TLR-7 stimulation drove higher TNF-related apoptosis-inducing ligand (TRAIL) expression in pDCs. Additionally, TLR-7- and TLR-9-stimulated pDCs exhibited a mature phenotype, improving the antigen presentation and lymph node homing-related markers. In conclusion, pDCs could serve as a drug target against HCV in order to improve antiviral activity and as an enhancer of viral immunization.IMPORTANCE We implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs' behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-α, but also through additional mechanisms associated with pDC maturation. We provided evidence that TLR agonists can enhance antiviral pDCs' function and can induce phenotypic changes that may facilitate the interplay with other immune cells. These findings suggest the possibility of including TLR agonists in the strategies of HCV vaccine development.
Subject(s)
Dendritic Cells/immunology , Hepacivirus/immunology , Hepatitis C/immunology , Interferon-alpha/pharmacology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 9/agonists , Virus Replication/drug effects , Antiviral Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/virology , Dendritic Cells/drug effects , Dendritic Cells/virology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/immunology , Liver Neoplasms/virology , Tumor Cells, CulturedABSTRACT
BACKGROUND: NRTIs-sparing regimens exert favourable profiles on T-cell homeostasis associated parameters. Our aim was to analyze the effect of NRTIs sparing regimen (NRTI-sparing-cART) vs NRTIs-containing regimen (NRTI-cART), on T-cell homeostasis associated parameters in naive HIV-infected patients. METHODS: Biomarkers of cell survival (CD127) and replicative senescence (CD57), were measured by multiparametric flow cytometry for T-cell phenotyping on peripheral blood mononuclear cells (PBMCs) samples just before (baseline) and after 48 weeks of undetectable viral load in patients on NRTI-sparing-cART (N = 13) and NRTI-cART (N = 14). After 48 weeks a subgroup of patients (n = 5) on NRTI-cART switched to NRTI-sparing-cART for another additional 48 weeks. In vitro assays were performed on PBMCs from HIV-uninfected healthy donors exposed or not to HIV. To analyze the independent factors associated with type of cART bivariate and stepwise multivariate analysis were performed after adjusting for basal CD4+, CD8+ and nadir CD4+ T-cell counts. RESULTS: After 48 weeks of a NRTI-sparing-cART vs NRTI-cART patients have higher effector memory (EM) CD4+ CD127+ T-cell levels, lower EM CD4+ CD57+ T-cell levels, higher CD8+ CD127+ T-cell levels, lower CD8+ CD57+ T-cell levels and higher memory CD8+ T-cell levels. This effect was confirmed in the subgroup of patients who switched to NRTI-sparing-cART. In vitro assays confirmed that the deleterious effect of a NRTIs-containing regimen was due to NRTIs. CONCLUSIONS: The implementation of NRTI-sparing regimens, with a favourable profile in CD127 and CD57 T-cell expression, could benefit cART-patients. These results could have potential implications in a decrease in the number of Non-AIDS events.
Subject(s)
CD57 Antigens/metabolism , HIV Infections/drug therapy , HIV Infections/immunology , Interleukin-7 Receptor alpha Subunit/metabolism , Reverse Transcriptase Inhibitors/therapeutic use , T-Lymphocytes/metabolism , Adult , Drug Therapy, Combination , Female , Homeostasis , Humans , Male , Middle AgedABSTRACT
We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.
Subject(s)
Antiretroviral Therapy, Highly Active/methods , CD4-CD8 Ratio , CD8-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV Infections/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Anti-HIV Agents/therapeutic use , Biomarkers/metabolism , Cell Survival/drug effects , Didanosine/therapeutic use , Female , Humans , Male , Middle Aged , Receptors, CXCR4/immunology , Stavudine/therapeutic use , Viral Load , Zalcitabine/therapeutic use , Zidovudine/therapeutic useABSTRACT
BACKGROUND: Several host factors contribute to human immunodeficiency virus (HIV) disease progression in the absence of combination antiretroviral therapy (cART). Among them, the CC-chemokine receptor 5 (CCR5) is known to be the main co-receptor used by HIV-1 to enter target cells during the early stages of an HIV-1 infection. OBJECTIVE: We evaluated the association of CCR5(WT/Δ32) heterozygosity with HIV-1 reservoir size, lymphocyte differentiation, activation and immunosenescence in adolescents and young adults with perinatally acquired HIV infection receiving cART. METHODS: CCR5 genotype was analysed in 242 patients with vertically transmitted HIV-1 infection from Paediatric Spanish AIDS Research Network Cohort (coRISpe). Proviral HIV-1 DNA was quantified by digital-droplet PCR, and T-cell phenotype was evaluated by flow cytometry in a subset of 24 patients (ten with CCR5(Δ32/WT) genotype and 14 with CCR5(WT/WT) genotype). RESULTS: Twenty-three patients were heterozygous for the Δ32 genotype but none was homozygous for the mutated CCR5 allele. We observed no difference in the HIV-1 reservoir size (455 and 578 copies of HIV-1 DNA per million CD4+ T cells in individuals with CCR5(WT/WT) and CCR5(Δ32/WT) genotypes, respectively; p 0.75) or in the immune activation markers between both genotype groups. However, we found that total HIV-1 DNA in CD4+ T cells correlated with the percentage of memory CD4+ T cells: a direct correlation in CCR5(WT/Δ32) patients but an inverse correlation in those with the CCR5(WT/WT) genotype. CONCLUSIONS: This finding suggests a differential distribution of the viral reservoir compartment in CCR5(WT/Δ32) patients with perinatal HIV infection, which is a characteristic that may affect the design of strategies for reservoir elimination.
Subject(s)
Acquired Immunodeficiency Syndrome/diagnosis , CD4-Positive T-Lymphocytes/virology , HIV Infections/diagnosis , Receptors, CCR5/genetics , Viral Load , Adolescent , Child , Child, Preschool , DNA, Viral/isolation & purification , Female , Genotyping Techniques , HIV-1 , Humans , Male , Pregnancy , Retrospective Studies , Young AdultABSTRACT
Introduction. SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. Materials and methods. Italian and Spanish metastatic INES patients data are reported. SPSS 20.0 was used for statistical analysis. Results. Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. Conclusions. The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data (AU)
No disponible
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Neuroblastoma/complications , Neuroblastoma/diagnosis , Neoplasm Metastasis/diagnosis , Neoplasm Metastasis/physiopathology , Eligibility Determination/standards , Prognosis , Clinical Protocols , 28599 , Survivorship/physiology , Informed Consent/standardsABSTRACT
INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.
Subject(s)
Biomarkers, Tumor/genetics , Clinical Trials as Topic , Gene Amplification , N-Myc Proto-Oncogene Protein/genetics , Neuroblastoma/mortality , Child , Child, Preschool , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Neoplasm Staging , Neuroblastoma/genetics , Neuroblastoma/secondary , Neuroblastoma/therapy , Prognosis , Survival RateABSTRACT
BACKGROUND: The persistence of an inverted CD4/CD8 ratio has been extensively associated with the increased morbimortality of chronic human immunodeficiency virus (HIV)-infected subjects. Thymic function is crucial for the maintenance of T cell homeostasis. We explored the impact of thymic function on the CD4/CD8 ratio of HIV-infected subjects. METHODS: In a cohort of 53 antiretroviral-naive HIV-infected subjects, the measure of thymic volume, as a representative marker for thymic function, was available at baseline and at 12, 24, and 48 weeks post antiretroviral treatment. RESULTS: Baseline thymic volume was associated with the CD4/CD8 ratio ( Ρ: = 0.413, P = .002), being this association highly dependent on the CD4 T cell levels. In subjects who achieved undetectable viral load after treatment (n = 33), a higher baseline thymic volume was associated with a higher increase in CD4 T cell counts and a decreasing trend in CD8 T cell counts during follow-up. Moreover, the baseline thymic volume was independently associated with the normalization of the CD4/CD8 ratio after 96 weeks of treatment (odds ratio, 95% confidence interval: 1.95 (1.07-3.55); P = .03). CONCLUSIONS: Our data indicate the relevance of the remaining thymic function before the start of treatment to the CD4/CD8 ratio of HIV- infected subjects and, hence, potentially, in their clinical progression.
Subject(s)
CD4-CD8 Ratio , HIV Infections/immunology , HIV Infections/virology , HIV-1/immunology , Thymus Gland/anatomy & histology , Thymus Gland/physiology , Adult , Antiretroviral Therapy, Highly Active , Biomarkers , CD4 Lymphocyte Count , Female , HIV Infections/blood , HIV Infections/drug therapy , Humans , Immunophenotyping , Male , Organ Size , Phenotype , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Thymus Gland/diagnostic imaging , Tomography, X-Ray Computed , Treatment Outcome , Viral LoadABSTRACT
Background: HIV-1-controllers maintain HIV-1 viremia at low levels (normally <2000 HIV-RNA copies/mL) without antiretroviral treatment. However, some HIV-1-controllers have evidence of immunologic progression with marked CD4+T-cell decline. We investigated host genetic factors associated with protection against CD4+T-cell loss in HIV-1-controllers. Methods: We analysed the association of interferon lambda 4 (IFNL4)-related polymorphisms and HLA-B haplotypes within Long Term Non-Progressor HIV-1-controllers ((LTNP-C), defined by maintaining CD4+T-cells counts >500 cells/mm3 for more than 7 years after HIV-1 diagnosis) versus non-LTNP-C, who developed CD4+T-cells counts <500 cells/mm3 Both a Spanish study cohort (n=140) and an international validation cohort (n=914) were examined. Additionally, in a subgroup of individuals HIV-1-specific T-cell responses and soluble cytokines were analysed RESULTS: HLA-B*57 was independently associated with the LTNP-C phenotype (OR=3.056 (1.029-9.069) p=0.044 and OR=1.924 (1.252-2.957) p=0.003) while IFNL4 genotypes represented independent factors for becoming non-LTNP-C (TT/TT, ss469415590, OR=0.401 (0.171-0.942) p=0.036 or A/A, rs12980275, OR=0.637 (0.434-0.934) p=0.021) in the Spanish and validation cohort, respectively, after adjusting for sex, age at HIV-1 diagnosis, IFNL4-related polymorphisms and different HLA-B haplotypes. LTNP-C showed lower plasma IP-10 (p=0.019) and higher IFN-γ (p=0.02) levels than the HIV-1-controllers with diminished CD4+T-cell numbers. Moreover, LTNP-C exhibited higher quantities of IL2+CD57- and IFN-γ+CD57- HIV-1-specific CD8+T-cells (p=0.002 and 0.041, respectively) than non-LTNP-C. Conclusions: We have defined genetic markers able to segregate stable HIV-1-controllers from those who experience CD4+T-cell decline. These findings allow for identification of HIV-1-controllers at risk for immunologic progression, and provide avenues for personalized therapeutic interventions and precision medicine for optimizing clinical care of these individuals.
Subject(s)
Genetic Predisposition to Disease/genetics , HIV Infections/genetics , HLA-B Antigens/genetics , Interleukins/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Cohort Studies , Disease Progression , Female , Genetic Predisposition to Disease/epidemiology , HIV Infections/epidemiology , HIV-1 , Humans , Male , Young AdultABSTRACT
TROCAI is a phenotypic tropism test developed using the virological response to a short-term exposure to maraviroc monotherapy (Maraviroc Clinical Test [MCT]). It was found that with TROCAI, a cutoff of <0.5% of dual/mixed viruses was needed to predict R5 HIV tropism. Here, we have validated TROCAI, using this cutoff, in a new cohort of 42 patients, finding a very high concordance between TROCAI and MCT (98%), and a good concordance (71 to 87%) with other genotypic/phenotypic methods.
Subject(s)
Cyclohexanes/pharmacology , HIV Fusion Inhibitors/pharmacology , HIV/drug effects , Triazoles/pharmacology , Viral Tropism/drug effects , Virology/methods , HIV/physiology , Humans , Inhibitory Concentration 50 , Maraviroc , Viral Tropism/physiologyABSTRACT
OBJECTIVES: Pre-operative anemia has been associated with increased post-operative morbidity and mortality in elective cardiac surgery, but its association with post-operative mortality after open or endovascular surgery for critical limb ischemia (CLI) is not well established. The aim of this study was to evaluate the relationship between pre-operative anemia and mortality in surgery for CLI. MATERIALS AND METHODS: A retrospective study of 403 consecutive patients (mean age = 73; 73% male) undergoing open (n = 191, 47%) or endovascular (n = 212, 53%) surgery for CLI between 2005 and 2013 was performed. Neither redo revascularization procedures (ipsilateral or contralateral) nor acute limb ischemia patients were included as new cases. RESULTS: The best cut off (receiver operating characteristic curve) that related pre-operative hemoglobin to mortality was 10 g/dL. The immediate (in hospital or < 30 days) mortality rate was 8% (32 patients), with no significant differences between open and endovascular surgery. Patients with a pre-operative hemoglobin <10 g/dl had a higher immediate mortality rate (17.7% vs. 5.1%), with a risk (OR), adjusted by age and prior myocardial infarction, of 3.9, 95% CI 1.8-8.4 (p = 0.001). The mean follow up of the cohort was 30 months (97% complete). Similarly, a pre-operative hemoglobin <10 g/dL was significantly associated with a lower 1 year (55 vs. 83%) and 5 year survival rate (21 vs. 53%) with an associated risk (HR) of 2.5, 95% CI 1.8-3.4 (p < 0.001) adjusted by age, previous myocardial infarction, chronic renal failure, stroke, diabetes mellitus, and ischemic ulcers. CONCLUSIONS: Pre-operative anemia is a risk factor for immediate and late mortality among patients with CLI, regardless of other risk factors and the type of revascularization technique. Prospective studies are needed to evaluate the potential effect of its treatment on survival outcomes.
Subject(s)
Anemia/mortality , Endovascular Procedures/mortality , Ischemia/therapy , Peripheral Arterial Disease/therapy , Vascular Surgical Procedures/mortality , Aged , Aged, 80 and over , Anemia/blood , Anemia/complications , Anemia/diagnosis , Area Under Curve , Biomarkers/blood , Chi-Square Distribution , Critical Illness , Endovascular Procedures/adverse effects , Female , Hemoglobins/metabolism , Humans , Ischemia/complications , Ischemia/diagnosis , Ischemia/mortality , Ischemia/surgery , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Peripheral Arterial Disease/complications , Peripheral Arterial Disease/diagnosis , Peripheral Arterial Disease/mortality , Peripheral Arterial Disease/surgery , Predictive Value of Tests , Proportional Hazards Models , ROC Curve , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Vascular Surgical Procedures/adverse effectsABSTRACT
Regulatory T (Treg) cells comprise different functional subsets with different CCR5 expression. Treg homeostasis is disrupted by HIV but the effect of treatment has barely been explored. In a longitudinal design, we compared the effect of a maraviroc-containing (n = 9) or sparing (n = 12) therapy in antiretroviral-naive HIV-positive participants on peripheral FoxP3(low) CD45RA(+) (nTreg), FoxP3(high) CD45RA(-) (eTreg) and FoxP3(low) CD45RA(-) (non-Treg) cells. Maraviroc significantly reduced all subsets in the short-term and, except for nTreg cells, also normalized them in the long-term. The correlation between eTreg cells and CD4 counts, lost before treatment, was only restored by maraviroc. The differential effect of maraviroc on Treg subsets contributes to understanding its immunomodulatory effects.
Subject(s)
CCR5 Receptor Antagonists/therapeutic use , Cyclohexanes/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , Homeostasis , T-Lymphocytes, Regulatory/immunology , Triazoles/therapeutic use , CD4 Lymphocyte Count , Forkhead Transcription Factors/analysis , Humans , Immunophenotyping , Leukocyte Common Antigens/analysis , Longitudinal Studies , Maraviroc , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/chemistryABSTRACT
BACKGROUND: Despite the relevance of monocytes as promoters of the inflammatory response, whether human immunodeficiency virus (HIV) infection induces premature age-related changes to the phenotype and function of monocytes or whether these alterations are different and/or specifically driven by HIV remains to be mechanistically determined. METHODS: We assayed the activation phenotype and the responsiveness in vitro to Toll-like receptor (TLR) agonists in classical, intermediate, and nonclassical subsets of monocytes by assessing intracellular interleukin 1α (IL-1α), IL-1ß, interleukin 6 (IL-6), interleukin 8, tumor necrosis factor α, and interleukin 10 (IL-10) production in 20 HIV-infected patients receiving combination antiretroviral therapy (cART) and 2 groups of uninfected controls (20 age-matched young individuals and 20 older individuals aged >65 years). RESULTS: HIV-infected patients showed a more activated phenotype of monocytes than older controls. Regarding functionality, under unstimulated conditions HIV-infected patients showed a higher percentage of classical monocytes producing IL-6 and IL-10 than control subjects. The percentage of cells with production of multiple cytokines (polyfunctionality), including IL-10, in response to TLR agonists was greater among HIV-infected patients than among control subjects. CONCLUSIONS: Inflammatory alterations associated with monocytes during HIV infection are different from those in aging individuals. This monocyte dysfunction, mainly characterized by high levels of IL-6- and IL-10-producing monocytes, may have clinical implications in HIV-infected patients that are different from those in aging individuals.
